Project Summary/Abstract The reactivity of organic radicals endows these species with the potential to mediate otherwise inaccessible transformations. This potential, however, has not been fully met in synthetic applications because the selectivity of these fleeting intermediates is exceedingly difficult to control. Nature, on the other hand, has evolved a strategy for generating and controlling a single radical to carry out a dizzying variety of challenging bond activations within the largest known enzyme superfamily, radical S-adenosyl-methionine (SAM) enzymes. This chemistry is enabled by activation of a redox-inert electrophile (adenosine triphosphate) with a Lewis base (methionine) to generate a sulfonium cofactor (SAM). This cofactor binds in tightly regulated environment such that, upon sulfonium reduction, the resulting radical is poised to react in a manner dictated by weak interactions in the enzyme active site. The research proposed in this application aims to mimic this method of generating and controlling these reactive species to harness the full potential of radical intermediates in synthetic chemistry. The proposed means of achieving this outcome involves activation of mild and readily available electrophiles (alkyl-carboxylates) by cooperative Lewis-base activation and anion-abstraction to generate ion-paired sulfonium intermediates in a pre-organized, chiral environment. Upon single-electron reduction, the resulting radical will react with selectivity controlled by attractive non-covalent interactions that were templated in the sulfonium precursor. By mimicking the mechanism that enables radical SAM enzymes to tame reactive intermediates, the proposed catalysts will provide an unprecedented degree of catalyst control over the reactivity of organic radicals.